Norganic Chemistry in Nuclear Imaging and Radiotherapy - Current and Future Direction

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Radiochim Acta. Author manuscript; available in PMC 2014 November 06.
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Radiochim Acta. 2012 August ; 100(8-9): 653667. doi:10.1524/ract.2012.1964.
Inorganic chemistry in nuclear imaging and radiotherapy:

current and future directions
Valerie Carroll1, Dustin W. Demoin1, Timothy J Hoffman1,2,3, and Silvia S Jurisson1,*
1Chemistry, University of Missouri, Columbia, MO 65211, USA
2Internal Medicine, University of Missouri, Columbia, MO 65211, USA
3Harry S Truman Memorial Veterans Hospital, Columbia, MO 65211, USA
Summary
Radiometals play an important role in diagnostic and therapeutic radiopharmaceuticals. This field
of radiochemistry is multidisciplinary, involving radiometal production, separation of the
radiometal from its target, chelate design for complexing the radiometal in a biologically stable
environment, specific targeting of the radiometal to its in vivo site, and nuclear imaging and/or
radiotherapy applications of the resultant radiopharmaceutical. The critical importance of
inorganic chemistry in the design and application of radiometal-containing imaging and therapy
agents is described from a historical perspective to future directions.
Keywords
Radiometals; Bifunctional chelates; Specific targeting; Nuclear imaging; Radiotherapy
Introduction
The application of radioisotopes of inorganic elements to nuclear medicine, both diagnostic
and therapeutic, has been of interest almost since the discovery of radioactivity. The middle
to late 1930s saw the development of radionuclides with potential medical applications
with 32P, 131I, and 89Sr and the first human studies for leukemia, thyroid and bone therapy,
respectively, were initiated [1]. Since the early studies, many diagnostic and some
therapeutic radiopharmaceuticals have been developed. Diagnostic nuclear imaging requires
the use of penetrating radiations from radionuclides that emit either gamma rays or
annihilation photons from positron emission. Radiotherapy requires particulate emission
from alpha or beta decay (although there is some interest in Auger electrons) so that the
energy of decay is deposited over a relatively short range (e.g., in the cancer cells). The
development of the 99Mo/99mTc generator in the late 1950s led to the predominance
of 99mTc in diagnostic nuclear medicine and was the entry into the field of radiometal based
imaging and therapeutic radiopharmaceuticals [2, 3]. Recent shortages of 99Mo have
brought to light the precarious position of the field of nuclear medicine because of its
dependence on aging reactors for production of 99Mo [4].
*
Author for correspondence. jurissons@missouri.edu; This author is a member of the Editorial Advisory Board of this journal. Editor..
Carroll et al. Page 2
Many excellent reviews (and the references therein) covering the production of
radionuclides for medical applications[510] and the state of diagnostic and therapeutic
radiopharmaceuticals[9, 1125] have been published over the last 20 years. Here we
describe the current status and trends in inorganic radiopharmaceutical chemistry and future
directions. We have elected to not include those radiometals whose use is strictly as the aqua
ions (e.g., 82Rb+, 201Tl+. 89Sr2+) and to focus on those with reasonable half-lives for
shipping or that are available in generator form.
Radiometals in radiopharmaceuticals
Radiometals have become an integral component of many radiopharmaceuticals because
their nuclear properties (Table 1)[26] are more suitable for diagnostic and therapeutic
nuclear medicine applications than those of their Main Group non-metal radionuclides. Not
only are the nuclear emissions (, , +, ) and their energies and half-lives important, but
their availability and cost are more often the determining factors in their application for
routine medical use. Additionally, there is a requirement for high specific activity (activity
per unit mass) for many medical applications, particularly those involving receptor targeted
radiopharmaceuticals. An excellent example illustrating these concepts is the advent of
the 99Mo/99mTc generator, which made the 6 h, high specific activity Tc-99m widely
available at a reasonable cost.
Radiometals offer an advantage over radiolabeling organic molecules (e.g., with 18F, 11C,
etc.) in that lyophilized kit formulations, which allow rapid radiolabeling, are often
available. The radiopharmaceutical kits contain all ingredients except for the radiometal.
To formulate the final radiopharmaceutical, the radiometal is added to the kit and the
instructions (e.g., let stand at room temperature for 30 minutes, heat in a boiling water bath
for 30 minutes, etc.) are followed, quality control is performed typically resulting in product
yields greater than 90%, which are suitable for patient administration. An example of a kit
formulation is that for Cardiolite (Figure 1), which is clinically approved for myocardial
imaging and requires the addition of 99mTc pertechnetate and heating.
The radiometals listed in Table 1 include some of the more widely used and potentially
useful radionuclides for either diagnostic imaging or radiotherapy. There is no ideal
diagnostic radiometal and no ideal therapeutic radiometal; each has its own unique benefits
and associated problems. Technetium-99m was considered to be the ideal diagnostic

radionuclide for many years because of its widespread availability, low cost, and relatively
easy product formulations. The recent shortages of 99mTc have made the nuclear medicine
field consider alternatives as it is not clear that the issues that led to the shortage will be
solved. Not only are the aging reactors that make fission 99Mo an issue, but so are concerns
of non-proliferation shifting the field to consider conversion to low enriched 235U or moving
toward 98Mo(n,) production of 99Mo. Low enriched 235U fuel will require irradiation of
higher masses of uranium fuel to obtain the same activity (quantity) of 99Mo, which will
require modifications to the separation method and likely higher radioactive waste
generation. The 98Mo(n,) production of 99Mo will result in lower specific activity 99Mo
(i.e., more mass because 98Mo would not be separated from 99Mo) and thus a larger or
different generator system would be required.

The various radiometals listed in Table 1 have excellent nuclear properties for nuclear
medicine applications. Their chemical properties (substitution rates (both on and off), redox
chemistry, hydrolysis rates, etc.) on the radiotracer level, where the radiometal is often nM
in concentration or lower, pose challenges. The availability of a matched pair of

radionuclides, one for diagnosis and one for therapy, would be of value but is rarely
available. True matched pairs would include different radioisotopes of the same element as
with the diagnostic radionuclide 64Cu and the therapeutic radionuclide 67Cu. Pseudo-
matched pairs would involve radioisotopes of similar but different elements as with the
diagnostic radionuclide 99m Tc and the therapeutic radionuclides 188/186Re. Indium-111
analogues have been used as an ersatz diagnostic matched pair for the
radiotherapeutic 90Y (which has no imageable emission), however the inorganic
chemistry, in vivo chemistry, and in vivo pharmacokinetics of the 111In product may be
different from that of the analogous 90Y product depending on the chelate and their relative
kinetic stabilities. Thus, particular caution must be applied with matched pairs if the
radiometals are not the same element.
Targeting strategies for radiometal conjugates

The current driving force behind the clinical application of radiopharmaceuticals in nuclear
medicine is the ability to selectively direct, or target, radiolabeled molecules to active sites
of human disease. In order to effectively accomplish this goal, a suitable diagnostic or
therapeutic radiometal must be strategically attached to a biological targeting vector. Figure
2 illustrates a general schematic of the most common approach to a targeted
radiopharmaceutical using a suitable bifunctional chelating agent (BFCA) directly linked to
a biological targeting vector. Although direct labeling (with Tc and Re) has been reported,
the labeling is generally non-specific and used primarily for antibody labeling. This
discussion will be limited to the BFCA approach only.
The BFCA serves the dual purpose of providing a means to stably complex the radiometal
and also allows for selective attachment directly to the selected biological targeting vector.
A widely employed strategy for linking or conjugation of a BFCA to a biological targeting
vector involves coupling a free primary amine (or activated carboxylic acid) located on the
structure of the BFCA with an activated carboxylic acid (or primary amine) from the
biological targeting vector to generate a stable amide bond linkage. In some cases, BFCA
conjugation to a biological targeting vector requires the addition of an organic linking group
in order to maximize in vivo targeting, or alter non-target tissue pharmacokinetics [27]. A
variety of linking groups have been successfully employed including simple multi-amino
acid linkages, aliphatic carbon chain linkages, and small organic heterocyclic compounds
[27]. In all cases, the goal has been to generate a combination of radiometal, BFCA, and
linking technology that results in a radiopharmaceutical to selectively target a human disease
process while minimizing non-disease and non-target tissue background accumulation of
radioactivity.
Numerous strategies for developing targeted radiopharmaceuticals have been employed over
the past several decades, including the radiolabeling of small proteins, antibodies, antibody
fragments, peptides, and small organic molecules [2732]. For the purpose of this

discussion, we are limiting our scope to focus only on peptide targeting vectors, which have
either recently shown clinical potential, or are currently being investigated pre-clinically for
their future use as targeted radiopharmaceuticals [3239]. Peptides, as a class in themselves,
offer tremendous flexibility for modification when biological issues such as in vivo
clearance kinetics and metabolic stability are taken into consideration. Further supporting
the use of peptides as selective biological targeting vectors is the increasing evidence of the
presence and up-regulation of various peptide receptors associated with human cancers.
Table 2 provides an overview of various peptides and their respective receptor families
currently under development for use as the biological targeting vector component of site
directed radiopharmaceuticals. The list was selected based on current interest and use in the
development of targeted radiopharmaceuticals where a significant body of literature is being
assembled supporting the validity of these radiolabeled peptides including positive results
upon in vitro evaluation, animal model biodistribution studies, animal model in vivo
imaging, and in several cases human patient studies [32, 37]. Several of the peptide targeting
vectors listed have undergone extensive evaluation as potential radiopharmaceuticals
resulting in anywhere from thirty to several hundred unique peptide targeting vectors
radiolabeled to obtain an optimum candidate for potential clinical evaluation [32, 37].
An example of a bioconjugate under current investigation is the bombesin peptide

conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). These
peptide targeting vectors have been conjugated with a variety of bifunctional chelating
agents in order to complex and evaluate the spectrum of radiometals available for diagnostic
and therapeutic radiopharmaceutical development [40].
Radiometal chelate considerations

Numerous chelates have been developed and evaluated for various radiometals as the basis
of BFCAs that can be appended to biomolecules for targeting. It is clear that both
thermodynamic and kinetic stability of the resultant radiometal complexes are important for
the development of safe and efficacious radiopharmaceuticals, with kinetic stability being
more important under the high dilution on injection in vivo [41, 42]. The dissociation rate
(koff) will determine in vivo stability (Ks = kon/koff) since equilibrium conditions are no
longer applicable once the radiopharmaceutical has distributed throughout the blood volume.
Any loss of the radiometal from its chelate in vivo leads to undesirable and higher non-target
irradiation. Some radiometals additionally require the BFCA to provide redox stability to
oxidation and/or reduction. Technetium and rhenium complexes are examples where the
radiometal can be susceptible to in vivo oxidation to pertechnetate or perrhenate, while
Cu(II) and Au(III) complexes are examples where the radiometals can be susceptible to
reduction to either Cu(I) or Au(0); in all cases specific targeting is lost. There is no universal
chelate that will function as the best BFCA for all radiometals. Each metal, in a given
oxidation state, has its own unique and specific requirements for which donor atoms will
yield sufficiently kinetically inert radiometal complexes for in vivo applications. Below we
discuss the radiometals that we consider potentially the most useful for site directed
radiopharmaceuticals in which peptides act as the targeting moiety.

Technetium
The availability of technetium (as pertechnetate, TcO41) from a relatively
inexpensive 99Mo/99mTc generator, together with its nuclear properties, which are ideal for
SPECT imaging, has made 99mTc the workhorse of the nuclear imaging community.
Technetium is situated in the middle of the d-block transition elements in Group 7 between
manganese and rhenium, and this position gives the metals in this triad one of the wider
ranges of available oxidation states. Compounds of Tc have been reported in oxidation states
ranging from +7 to 1, with Tc(V), Tc(III) and Tc(I) most commonly utilized in nuclear
medicine applications. Over the years, many Tc complexes in a variety of oxidations states
with a multitude of chelators have been synthesized and evaluated in vivo. The seminal
work of Deutsch and Davison in the late 1970s and 1980s demonstrated the importance of
Tc-99 inorganic chemistry to radiopharmaceutical development [4348]. The chemistry of
technetium labeled radiopharmaceuticals has been extensively reviewed and a few examples
are shown in Figure 3 [27, 49, 50].
Currently there are numerous clinically approved radiopharmaceuticals based on 99mTc that
are essentially small molecules and not based on the bifunctional chelate approach.
Technetium(V) is the most accessible oxidation state from Tc(VII) as evidenced by the
many approved Tc(V) radiopharmaceuticals such as Neurolite, Ceretec, Myoview and

MAG3 (Figure 3), which are approved for cerebral blood flow imaging, cerebral blood
flow imaging and white blood cell labeling, myocardial perfusion, and renal filtration
imaging, respectively. Current interest in small molecule 99mTc radiopharmaceutical
development is in the area of potential myocardial perfusion imaging agents with faster liver
clearance than the current agents (Cardiolite and Myoview). Duatti and co-workers
developed the neutral 99mTcN-NOET (Figure 4A), which contains the Tc-nitrido core and
two N-ethyl-N-ethoxydithiocarbamates bound to the Tc(V) center[51, 52]. Evaluation in
humans showed faster liver clearance [51]. Duatti, Tisato, Liu and Santos have all reported
+1 cationic analogs in which one of the dithiocarbamate moieties is replaced with a
tridentate PNP donor set (Figure 4B); addition of various ether groups were evaluated for
the effect(s) on clearance [5358].
Pertechnetate as eluted from the 99Mo/99mTc generator behaves similarly to iodide, being
taken up by the thyroid and excreted through the renal-urinary system. This rapid excretion
of pertechnetate can be considered a benefit as this is the chemical species that will be
generated by in vivo instability or metabolism of technetium complexes in lower oxidation
states. As Tc(VII) in pertechnetate is coordinatively saturated, it is reduced during
radiopharmaceutical preparations to generate stable radiometal complexes for in vivo
applications.
Technetium(V) has a d2 electronic configuration and is dominated by oxo chemistry in

aqueous solution. These complexes tend to be either mono-oxo with square pyramidal or
distorted octahedral geometries, or dioxo with octahedral geometry; examples of both are
shown in Figure 3. Technetium(V) is easily accessible from pertechnetate (Tc(VII)), and
radiopharmaceutical kit formulations often utilize Sn(II) as the reducing agent.
Glucoheptonate or citrate are used in kit formulations when the chelate is slow to react
compared to hydrolysis, which would result in the formation of colloidal TcO2 if a suitable

chelate is not present. A range of donor atoms, including N, S, P and O, have been used to
form Tc(V) complexes. Tetradentate chelates are generally used to make this somewhat
labile system more kinetically inert, and the most commonly used BFCAs include
mercaptoacetylglycylglycylglycine derivatives (N3S MAG3 derivatives), diaminedithiol or

amidoaminedithiol derivatives, the linear tetraamine 1, 4,8,11-tetraazaundecane (a 2-3-2
carbon backbone), and 6-hydrazinonicotinic acid (HYNIC) analogues [27, 59, 60]. The use
of the HYNIC BFCA for 99mTc is attractive because it involves a simple labeling procedure
for biomolecules without difficult chelate synthesis. However, HYNIC is generally a
monodentate BFCA and thus requires the use of co-ligands to satisfy the coordination sphere
of the Tc(V) center. Unfortunately, the co-ligands yielding the best pharmacokinetic
properties tend to form multiple products while those that form single entities (e.g., thiol,
phosphine donors) tend to be quite lipophilic with poor pharmacokinetics [6164]. Two
recent examples of Tc(V) complexes for targeting peptide receptors are 99mTc-depreotide
(diamido amine thiol [N3S] chelator linked to a somatostatin peptide)[65] and 99mTc-
HYNIC-GRP [63], both shown in Figure 5.
The nitrido core has been evaluated as an alternative to the oxo core typically utilized with
Tc(V) complexes. Duatti and Tisato utilized the PXP donor set along with bidentate (YZ)
ligands as potential bifunctional chelates; only the [TcN(PXP)(YZ)]0/+ (and no

[TcN(PXP)2]2+ or [TcN(YZ)2]0/2) formed at the 99mTc level making this a possible route to
radiolabeling peptides [66].
Technetium(III) with its low-spin d4electronic configuration is more kinetically inert than
Tc(V); however, Tc(III) requires additional reducing agent for access from Tc(VII)
pertechnetate and often higher temperatures. Technetium(III) has been shown to coordinate
to soft and hard donors (N, O, P, and S) in both octahedral (paramagnetic) and 7-coordinate
(diamagnetic) ligand environments. Teboroxime [TcCl(CDO)3BCH3] is an example of a
Tc(III) approved radiopharmaceutical for myocardial imaging (Figure 6). Very few Tc(III)
complexes have been evaluated as bifunctional chelates, with the 4+1 NS3/P system
showing some promise [67, 68]. The challenges with this system include the harsher
reducing conditions and controlling the higher lipophilicity associated with the sulfur and
phosphorus donor ligands.
The low-spin d6 electronic configuration of Tc(I) is kinetically inert and makes this
oxidation state desirable as the basis of new Tc radiopharmaceutical development. The

report by Alberto and co-workers demonstrating the accessibility of [Tc(CO)3(OH2)3]+ from
pertechnetate in aqueous solution accelerated interest in potential Tc(I) radiopharmaceuticals
[6972]. The three carbon monoxide ligands are inert to substitution while the three
coordinated water molecules offer an easy route for ligand exchange with a suitable
tridentate chelate. The current availability of the commercial IsoLink kit from Covidien
makes this a desirable starting complex for radiolabeling with 99mTc. This allows for
relatively fast exchange onto the Tc(I) center with a molecular targeting tridentate BFCA.
Tc(I) is considered a soft metal center and as such prefers soft donors, which tend to
make the resultant complex more lipophilic; however a balance must be achieved with
clearance properties from non-target tissues in vivo. Thus, amine, imine and carboxylate
donors are often used with the [Tc(CO)3]+ core to reduce lipophilicity and thus facilitate

clearance. Scorpionates [73], single amino acids (especially histadine analogues) [64], and
other chelates were initially investigated as potential chelators for the bifunctional chelate
approach for the [Tc(CO)3]+ core [7479]. A representation of these binding moieties for the
tricarbonyl core is given in Figure 7 [73, 75].
Benny and co-workers utilized click chemistry to improve radiolabeling efficiency of the
tricarbonyl technetium(I) core at lower temperatures than reported by Schibli et al. [75, 80]
to minimize potential damage to appended biological targeting vectors [81]. Two
approaches were reported that differed primarily in the order of radiolabeling the
[Tc(CO)3]+ core. One approach involved coupling the BFCA containing a pendant primary
alkyne with an azido moiety containing the biological targeting group and subsequently
radiolabeling it. The second approach involved radiolabeling the BFCA containing the
primary alkyne and then reacting it with the azido targeting moiety [81]. Both approaches
yielded the same product, but neither approach gave sufficient radiolabeling yields at 25C
at less than 105 M BFCA [81].
Although the availability of the Isolink kit has made this core easily accessible and the Tc(I)
oxidation state offers high kinetic stability, an inherent issue with the [Tc(CO)3]+ core has
been the resultant increased lipophilicity of its complexes. Increasing complex lipophilicity
results in increased and often slow hepatobiliary clearance, which hinders imaging the
pelvic/abdominal region.
Rhenium
Rhenium has been referred to as the radiotherapeutic matched pair for the diagnostic 99mTc.
Its position as the 3rd row congener of Tc in Group 7 makes its chemistry similar to that of
technetium in many ways, but there are differences which manifest themselves when redox
chemistry or substitution kinetics are involved. Rhenium is more difficult to reduce than Tc
and is slower to substitute. This leads to re-oxidation to perrhenate in vivo if the chelate
systems are not carefully selected. Fortunately, perrhenate clears from the body quickly and
thus does not accumulate in non-target organs/tissues. The slower substitution rates have led
to lower lability in the site trans to the oxo group in Re(V) complexes, which has resulted in
different products for Re(V) compared to Tc(V) [82]. The Re(V) complexes may have a
ligand in the site trans to the oxo group whereas Tc(V) does not or substitution slows down
reduction resulting in a completely different complex for Re(V) [82]. This may also be the
reason that a Re(V) complex of propyleneamine oxime analogues has not been reported (i.e.,
the Re analogue of Ceretec, Figure 3). Because reduction is more difficult for Re, the +5
oxidation state is the most accessible from perrhenate, although the ability to utilize the low
spin d6 tricarbonyl Re(I) core has received a lot of attention.
Rhenium(V) chemistry, like Tc(V), is dominated by oxo chemistry. Generally, chelators that
are NxS4-x donors have been utilized to complex and stabilize the oxorhenium(V) core [83].
Diamine dithiols (DADT), monamine monoamide dithiols (MAMA), and diamide dithiols
have all been shown to successfully chelate the oxorhenium (V) core and are most widely
used as potential BFCAs for Re(V). The susceptibility of Re(V) complexes to oxidation to
perrhenate on high dilution in vivo requires careful selection and testing of chelates for
Re(V); thiolate and phosphine donors seem to be most suitable at stabilizing Re(V) to

oxidation, perhaps because both are themselves reducing in nature. The N3S MAG3 type
chelates do not function as well with Re(V) on the radiotracer level (especially in vivo) as
they do with Tc(V) because oxidation is an issue. A second thiolate may add sufficient
stability although the N2S2 chelates tend to generate more lipophilic complexes.
Previous clinical trials have focused on the use of rhenium radiopharmaceuticals for the
palliation of metastatic bone cancer [8487], advanced lung cancer [88], and inoperable
hepatocellular carcinoma [89]. The majority of current research with Re(V) includes
potential use in bifunctional chelators, for example Re-N2S2-IMP 192 (Figure 8) [83, 90].
Since Re is more difficult to reduce than Tc, very few lower oxidation state complexes have
been evaluated on the radiotracer level. The 4+1 NS3/P type system for Re(III) has been
reported, however challenges exist in the reduction of 188ReO4 directly to Re(III) and a two
step formulation involving 188Re(EDTA) or 188Re(thiourea) complexes as the intermediate
has been investigated to minimize formation of colloidal reduced, hydrolyzed 188ReO2,
which arises from the amount of reducing agent necessary and the pH conditions required
for its synthesis [91].
As with Tc, the low spin d6 Re(I) oxidation state is kinetically inert and is currently being
investigated predominantly as a surrogate to Tc(I) tricarbonyl complexes on the macroscopic

level. Although reduction of perrhenate in aqueous solution to the +1 oxidation state is
difficult, it may be useful in the future for radiotherapeutic applications similar to those
imaging applications discovered for the technetium (I) tricarbonyl analogues [49, 73, 92,
93]. Valliant and co-workers have shown that the chemistry of tricarbonyl complexes with
Re(I) and Tc(I) carborane complexes may be different for some carboranes due to
differences in redox potentials of the two metals and perhaps to their differing substitution
rates [94].
The availability of high specific activity radiorhenium (186 or 188) is essential for the
development and approval of Re-based radiopharmaceuticals for radiotherapy. Although
a 188W/188Re generator is available, its routine availability is of question. The availability of
high specific activity 186Re would have a major impact for the field because the half-life and
beta energy of 186Re are more suitable for radiotherapeutic applications than those of 188Re.
Although production of 186Re from an accelerator is possible, it is currently not being
exploited [9599]. The longer half-life of 186Re would make it suitable for radiolabeling
antibodies or other longer circulating biomolecules.
Copper
Development of copper radiopharmaceuticals has received much attention due the
availability of multiple isotopes with radiopharmaceutical relevance [100]. The Cu isotopes
of most interest include 64Cu (imaging and therapy), 62Cu (imaging) and 67Cu (therapy) (see
Table 1). The Cu (II) oxidation state is preferred for radiopharmaceutical use as it is more
kinetically inert than the more common, yet labile Cu(I) oxidation state. Copper(II)
complexes tend to be Jahn-Teller distorted and kinetic lability remains an issue [101105].
Thus much research in this area addresses suitable chelates for kinetically inert, in vivo
stable Cu(II) complexes. Copper(II) is considered a borderline soft metal, favoring nitrogen

and oxygen donor groups; thiolates and phosphines tend to reduce Cu(II) to the more labile
Cu(I) unless care is taken. Early work in the development of a chelate system for Cu(II)
focused on DOTA and 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid, TETA;
however these complexes have demonstrated limited in vivo stability. Cross-bridged

derivatives of DOTA and TETA, CB-DO2A and CB-TE2A, as well as the sarcophagine
cage have proven more useful for chelation of Cu(II) for in vivo applications. BFCAs based
on cross-bridged derivatives of DOTA and TETA and the sarcophagine cage have proven
difficult to synthesize or easily modify and thus many investigators prefer to use the
commercially available DOTA analogues even though they are not sufficiently stable under
in vivo conditions. Brechbiel and co-workers have described a functionalized CB-TE2A
analog with a reported 13% yield from cross-bridged cyclam, which was subsequently
conjugated to RDG peptide analogs and labeled with 64Cu showing excellent in vitro
stability [106]. Additionally, these particular analogues are quite hydrophobic and
hepatobiliary clearance is often observed, leading to less than desirable pharmacokinetics.
Anderson and co-workers and references therein provide an excellent and comprehensive
recent review of copper radiopharmaceutical research [100].
Since last reviewed, two NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) Cu-64

conjugates[107110] have been reported. The 64Cu- NO2A-8-AOC-BBN(714)NH2

conjugate[110] and the 64Cu-NOTA-RGD-BBN conjugate[108, 109] were synthesized and
showed nM affinities for GRP and both v3 and GRP receptors, respectively. Both showed
favorable biodistribution results and PET imaging in tumor bearing mice. A subsequent
head-to-head study comparing 64Cu- NO2A-8-AOC-BBN(714)NH2, 64Cu-DOTA-8-AOC-
BBN(714)NH2, and 64Cu-CB-TE2A-8-AOC-BBN(714)NH2 was also reported;
while 64Cu-CB-TE2A-8-AOC-BBN(714)NH2 exhibited more favorable stability in vivo; a
reduced uptake and retention was observed in the tumor tissue compared to 64Cu- NO2A-8-
AOC-BBN(714)NH2 [107].
The NOTA chelate system may prove to be more suitable for Cu(II) than the analogous
DOTA or TETA systems, as the coordination number of Cu(II) is better matched. This
chelate system seems to form significantly more hydrophilic complexes with Cu(II) based
on the reports of Smith and Liu [107110]. Copper-64 is available to researchers on a
regular basis from a few sources; however 62Cu and especially 67Cu are not readily
available and it is questionable whether 67Cu will be available in sufficient quantities for
radiotherapy.
Recent studies with the small molecule 64CuATSM, which is taken up and retained in
hypoxic tissue [111], have focused on understanding the mechanism of uptake and retention
under reducing conditions. Fujibayashi et al. [111] reported that 64CuATSM not only is
retained in hypoxic cells but also cells having mitochondrial dysfunction with higher levels
of NADH and NADPH (reductases), even under normoxic conditions. Their findings
indicate that 64CuATSM may be more broadly applicable than other hypoxia imaging
compounds such as 18F-misonitroimidazole [111].

Gallium, indium, radiolanthanides, bismuth and actinium

Gallium, indium, the radiolanthanides, bismuth, and actinium have been grouped together
because the aminocarboxylate chelates have been utilized to stabilize these radiometals for
in vivo applications. These metals all form +3 cations and thus show some similarities in
their chemistries, although they differ in their coordination numbers and thus the optimal
chelate for in vivo stability. Gallium(III) is generally 6-coordinate, In(III) 6- to 8-coordinate
(usually 7-coordinate), Y(III) 6- to 12-coordinate (8- and 9-coordinate most common),
Ln(III) 6- to 12-coordinate (9-coordinate most common, but depends on the size of the metal
ion), and Bi(III) 6- to 8-coordinate. The primary criterion for in vivo stability of these metal
ions is to completely surround (saturate) their coordination sphere with donor atoms from
the appropriate chelator. DTPA (diethylenetriaminepentaacetic acid), DOTA, NOTA, and
various other amine carboxylate donor ligands have been used to complex these metal ions.
Too many or too few donor atoms within a chelate to fully saturate the coordination sphere
of the particular metal ion or a poor cavity fit between the chelate and the metal ion result in
an unstable complex in vivo.
Approved radiopharmaceuticals incorporating these radiometals include Quadramet

(153Sm-EDTMP) for bone pain palliation associated with metastatic disease (Figure 9A),
Octreoscan (111In-DTPA-octreotide) for imaging somatostatin receptor positive cancers

(Figure 9B), 67Ga-citrate for tumor imaging, 111In(oxine)3 for platelet imaging, 111In-
Prostascint for prostate cancer imaging, 111In-Oncoscint for colorectal and ovarian
cancer imaging, and 90Y-Zevalin for treating non-Hodgkins lymphoma, the last three all
incorporating monoclonal antibody targeting vectors.
Both DTPA and DOTA conjugated to antibodies or peptides have proven to be suitable
chelates for In(III) for in vivo applications. Conjugation of the peptide or antibody to DTPA
or DOTA through one of the carboxylate arms leaves the required 7-coordination sites
available for complexation to In(III). Indium-111 is readily available in high specific activity
and both DTPA and DOTA analogs are suitable for use as BFCAs [112]. The DTPA is often
the chelate of choice for In3+ because of its faster complex formation kinetics compared
with DOTA. Various aminecarboxylates (DTPA, DOTA, NOTA) have been evaluated along
with tris(2-mercaptobenzyl)amine and tris(2-hydroxybenzyl)amine chelates for Ga(III) [21,
40, 113]. Although studies utilizing DTPA and DOTA have been carried out for Ga(III),
neither is optimal for the smaller metal ion. The cavity size of DTPA and DOTA are
somewhat large for Ga(III) and its strong preference for forming 6-coordinate complexes
leaves dangling carboxylate arms. NOTA may have a better size and coordination number
for Ga(III) [114, 115]. The stability of the resultant radiometal complexes is important for
minimizing non-target tissue radiation doses and for obtaining suitable diagnostic images.
Gallium and indium, if lost from their chelator, will behave similarly in vivo to Fe(III) and
will be complexed by transferrin in the blood and localized to the liver. Much of the current
research for gallium and indium relies on the bifunctional chelate approach where the metal
is stably complexed to a chelator that is ligated to a biological molecule or biological
targeting vector, for example Octreoscan (111In- DTPA complexed to peptide) shown in
Figure 9B [34].

Several radiolanthanides have nuclear properties suitable for radiotherapy applications

including 153Sm, 177Lu, 149Pm, 166Dy, 166Ho and 161Tb (Table 1). The lanthanides are hard
Lewis acids and form primarily ionic bonds in aqueous solution. Thus, in order to form
complexes that are kinetically inert in vivo, they must be complexed with octadentate
macrocyclic chelates such as DOTA although some hindered DTPA analogues (e.g., CHX-
DTPA) have shown in vivo stability with radiolanthanides [116120]. Use of DOTA as a
BFCA may require either carbon backbone or aminocarboxylate arm derivatization to retain
the octadenticity of the DOTA analogue, although there are many studies using one of the
carboxylate arms for conjugation to the targeting agent [27, 116]. This derivatization is
necessary as the radiolanthanides show significant uptake in the skeleton (as a calcium
mimic) and the liver (where they are found as hydroxide colloids) in vivo if their complexes
are not sufficiently stable [27, 116, 117]. The aminophosphonate chelate
ethylenediaminetetramethylenephosphonic acid (EDTMP) was used to develop 153Sm-
EDTMP (Quadramet) as a bone pain palliation agent; 1,4,7,10-
tetraazacyclododecane-1,4,7,10-methylenephosphonic acid (DOTMP) has been investigated
more recently to form a more kinetically inert complex with 166Ho [116, 118]. Several
excellent reviews on the lanthanide chemistry of radiopharmaceuticals have been published
[27, 116, 117, 121].
Yttrium(III) is often considered a pseudo-lanthanide as it is situated above La(III) in Group

3. As 90Y has no gamma emissions (Table 1), researchers have often used 111In to assess its
in vivo biodistribution even though this is not ideal; when 90Y is lost from its chelate it
localizes primarily to bone, liver and other organs similar to the radiolanthanides [3],
while 111In localizes with transferrin to the liver. Yttrium and the radiolanthanides undergo
hydrolysis if they are lost from their chelate in the body resulting in colloidal M(OH)3,
which will accumulate in the liver and other blood rich organs; some of the radiometal will
localize in the bone if hydrolysis occurs more slowly [118]. Sterically hindered DTPA
analogs (CHX-DTPA and CyDTPA) have been determined to be suitable for 90Y labeling
with faster formation kinetics than DOTA [122126]. Yttrium-90-Zevalin (an antibody-
CHX-DTPA bifunctional chelator) is an example of a 90Y radiopharmaceutical currently in
clinical use [127, 128].
Bismuth(III) is of interest because two of its radioisotopes, 212Bi and 213Bi (Table 1), are
alpha emitters with tremendous potential for targeted radiotherapy [129131]. For
convenience, DTPA and DOTA analogues have been evaluated as chelators for Bi(III);
Brechbiel et al. recently reported on a decadentate DOTA analog, namely 3pC-DEPA,
which showed very good labeling yields with 205/206Bi at room temperature (~94% in 1 h)
and very good in vivo stability in mice [132]. Clinical studies of patients with advanced
myeloid leukemia showed the difficulties (loss of radiometal from chelate; short half-life)
and small successes (selected destruction of leukemia cells with few side effects) of targeted
alpha therapy from [213Bi]-HuM195 (a DTPA conjugated antibody) [129, 133, 134].
Because of the limited success of these initial studies, further clinical studies were extended
to [225Ac]-HuM195 to yield more dose per injected radiopharmaceutical from the
cumulative effects of all daughter product emissions [129, 133]. Any loss of bismuth from
its chelate would result in localization and predominant increased radiation exposure to the

kidneys [129]. Recently, Maecke and co-workers demonstrated the therapeutic potential of
a 213Bi labeled peptide, 213Bi-DOTA-PESIN as compared directly to the analogous 177Lu
labeled peptide, 177Lu-DOTA-PESIN [135]. The results from this preclinical study
conducted in a mouse model of prostate cancer clearly confirmed that therapy using 213Bi
was much more efficacious than therapy employing 177Lu in controlling tumor growth
while at the same time also confirming previous findings of marked kidney damage
associated with 213Bi therapy.
Actinium-225 has been suggested for use as an in vivo generator system for a decay chain
that would result in a therapeutic dose from 4 alphas and 2 betas, and includes 213Bi [129].
This additional therapeutic dose would be beneficial for treatment, but there is a risk that the
recoiling daughter nucleus would be lost from the chelator and result in undesirable non-
target irradiation in vivo unless the decay occurs inside the targeted cancer cell [136]. The
DOTA and DTPA chelates have been evaluated for 225Ac; if lost from its chelate, 225Ac
generally localizes in the liver or skeletal system in vivo, but proper chelation can reduce the
localization in non-target tissue [129, 136]. Several reviews have reported the benefits,
usefulness and challenges of actinium as a potential nanogenerator [129131, 133, 136
138].
The +3 radiometals have similarities in the BFCAs that are used with them; however there
are issues that need to be addressed for each in order for them to become clinically useful.
All of these radiometals are susceptible to hydrolysis and thus the reaction pH is critical for
their formation, especially at the radiotracer level; hydrolysis becomes an issue at least two
pH units earlier than at the macroscopic level and thus radiolabeling must be accomplished
under acidic conditions even though protons are released on complexation. The
commercially available 68Ge/68Ga generator makes 68Ga, a 68 minute positron emitter
readily available to the diagnostic nuclear medicine community. Although currently
available 68Ge/68Ga generator systems have 68Ge breakthrough issues, using suitable solid
phase ion exchange technology it is possible to further purify the eluted 68Ga [139, 140].
Gallium-67, a SPECT radionuclide, is available in high specific activity from accelerator
production on a routine basis although the gamma emission is not optimum for SPECT
image acquisition. There is no ideal chelator that has been identified for 67/68Ga3+ to date.
Recent reports with various nitrogen (amine and imine) and oxygen (carboxylate, phenolate,
hydroxamate) donor chelates suggest that perhaps the NOTA analogs will prove to be ideal,
however there has been no effort to determine the best donor atoms for Ga3+ [141, 142].
The radiolanthanides (and there are several of them with suitable nuclear properties; see
Table 1) have the advantage that a BFCA that is suitable for one of them should work for all
of them. Because their bonding is ionic in nature, octadentate macrocyclic DOTA analogs
are the ideal BFCA [116, 118, 143]. The issue of high specific activity production of
radiolanthanides must be addressed in order to promote routine use.
Bismuth radioisotopes suffer from availability, as does 225Ac. Although the alpha particles
emitted by these radionuclides have high cell killing potential, their routine availability
remains an issue for clinical use. Additionally, there has been very little, if any, chelate

design specifically for these two radiometals. DOTA has been the BFCA of choice without
consideration of other potential chelates (i.e., donors).
Zirconium
Zirconium has become of interest in the radiopharmaceutical arena because one of its
radioisotopes, 89Zr (Table 1), has nuclear properties suitable for use in PET imaging.
Zirconium is considered a labile, +4 metal ion with chemistry somewhat similar to that of
lutetium in that it is a hard metal center preferring hard, anionic oxygen donors [144].
Zirconium forms 8-coordinate complexes; however unlike the lanthanides that favor DOTA
and DTPA chelates, zirconium has been shown to be lost in vivo from these complexes
[145]. In fact, the stability constant (log KML) for Zr-DTPA is ~36 [40]; once again kinetics
is the dominant factor for in vivo stability. In vivo studies of 89Zr-ZrCl4 showed high liver
uptake, while 89Zr(C2O4)44 showed uptake in the skeletal system [145]. 89Zr can be
produced at a cyclotron and has been utilized as a PET radionuclide for labeling antibodies
and peptides (some using desferrioxamine as the chelator) [133, 146149]. A recent study
showed that 89Zr-desferrioxamine B-J591 can be used to successfully diagnose prostate
specific membrane antigen positive prostate tumors in vivo [145]. Although the availability
of a longer-lived positron emitter (3.26 days for 89Zr) would be beneficial by allowing
delayed PET imaging, the 100% abundance emission of a 909 keV gamma is not desirable;
and may be a significant deterrent.
Gold
Two radioisotopes of Au are of interest for radiotherapeutic applications, namely 198Au
and 199Au (Table 1). Gold-199 has more suitable beta and gamma emissions for nuclear
medicine applications and is available in high specific activity from an enriched Pt target.
The high abundance, higher energy gamma of 198Au (412 keV) makes it less favorable for
in vivo applications but it is more readily available for development. These two
radionuclides are readily available (both are reactor produced) to interested researchers.
Unfortunately, the chemistry of Au(III) is not straight-forward and both hydrolysis and
reduction to Au(0) are problems that need to be overcome. At the radiotracer level,
hydrolysis becomes an issue for Au(III) above pH 4; extracting (t-Bu4N)[198/199AuCl4] into
an organic solvent such as CHCl3 prior to reaction with the chelate addresses this issue
[150].
Recently, Bottenus and co-workers investigated a series of gold(III) bis-thiosemicarbazone

complexes [150]. Although one of the complexes reported, Au(3,4-HxTSE) (Figure 10),
showed favorable in vitro stability, biodistribution studies in CF-1 normal mice showed
>50% ID/g remaining in the bloodstream at 4 h p.i. with high lung uptake possibly resulting
from complex binding to serum albumin [150]. Stabilizing Au(III) to reduction under in
vivo conditions continues to be an issue that must be overcome to generate a potential 199Au
radiotherapeutic agent.
Gold-198 nanoparticles have received recent attention for potential radiotherapeutic

applications as in vivo reduction is not an issue. Gum Arabic coated nanoparticles
(GA-198AuNP) were formed by addition of an alanine based phosphine reducing agent

P(CH2NHCH(CH3)COOH)3 (THPAL) to a mixture of 198AuCl4 and Gum Arabic under

acidic conditions. Nanoparticle formation was accompanied by a color change from yellow
to purple, and TEM images indicated gold particle diameters in the range of 12 18 nm
[151153]. Animal studies in PC-3 tumor bearing SCID mice where GA-198AuNPs were
administered via intratumoral injection demonstrated slowed tumor growth when compared
to the non-radioactive treated control group [151].
Because of the difficulties encountered with Au(III) chemistry, the availability of suitable
chelates is limited. Design of a chelate to essentially encapsulate the Au(III) center so that
its axial sites are not available for attack and reduction may be what is needed. The chelate
itself must be stable to oxidation or Au(0) will form through internal redox chemistry.
Rhodium
Rhodium-105 is an interesting isotope for radiopharmaceutical use. Its moderate emission
is useful for therapeutic applications, while low abundance emissions are available for in
vivo mapping of the Rh-105 containing radiopharmaceutical as well as for dosimetry
determinations (Table 1). The low spin d6 electronic configuration of Rh(III) makes its
complexes kinetically inert. In fact, Rh(III) undergoes extremely slow water exchange (T1/2
~ 30 years), second only to its 3rd row congener Ir(III) [154]. This allows for formation of
metal chelate complexes with favorable in vivo stability. This high kinetic inertness is
overcome in substitution reactions by using refluxing alcohol (ethanol for biological
applications) to reduce Rh(III) to the more labile Rh(I) in situ to facilitate substitution;
carrying out the reactions in a normoxic atmosphere results in oxidation back to Rh(III)
following substitution [155].
Much of the early work towards development of a Rh-105 chelate system focused on
nitrogen and oxygen donor atoms such as cyclam and cyclen derivatives, amine oximes,
amine phenols, and amine porphyrin ligands [156, 157]. A variety of tetrathioether chelates
(macrocyclic and acyclic) have been evaluated and were shown to give 105Rh-S4 complexes
in >90% yield with high stability [157163]. Additionally, NS3, N2S2 and N4 macrocyclic
and N2S2 acyclic ligands were evaluated; although the complexes formed were very stable,
their yields dropped with increasing N donor atoms [161, 164167]. More recently, the
acyclic N2P2 and S2P2 chelates were evaluated for 105Rh complexation and again stabilities
were very high [168]. The macrocyclic S4 and acyclic N2S2 chelates conjugated to the
bombesin peptide BBN(714)NH2 with various linkers showed good binding to GRP
receptors, indicating promise for targeting prostate cancer [162, 164, 166]. Radiochemical
yields of >90% were achieved with many of the chelate systems that have been reported.
Overall, the presence of amine donor atoms increased the pH necessary for complexation
and resulted in lower yields at the radiotracer level due to the competing hydrolysis reaction;
the more amine N donors present, the higher the pH needed and the lower the yield [161,
164167]. The presence of phosphine donors allowed reduced temperatures and lower
concentrations of ethanol to be used at the radiotracer level (phosphine acts as both a
reducing agent and chelate) but at the expense of significantly higher ligand concentrations
(~1000 fold increase needed) [168]. Although higher temperatures and ethanol
concentrations are required for the tetrathioether chelate systems, they may prove to be more

suitable BFCAs due to ligand stability and the use of lower ligand concentrations for
generating the 105Rh bioconjugate. Based on literature reports to date, either the 222-S4 or
333-S4 acyclic ligand systems will be most useful as they each only generate one isomer on
complexation with Rh(III) (cis- and trans-dichloro, respectively) [159, 162].
Rhodium-105 is available in high specific activity. Its radiotracer complexes are kinetically
inert in vivo and thus transchelation will not be an issue. Its slow substitution kinetics can be
a hurdle in radiolabeling as higher temperatures are needed (e.g., refluxing ethanol) to
generate Rh(I) in situ to allow faster substitution [160, 163, 168]. The higher temperatures
required may be a problem for some biotargeting groups. As with many metals, hydrolysis is
an issue above pH 67 and this must be considered during any radiosyntheses.
Future directions
Inorganic chemistry will continue to play an important role in diagnostic and therapeutic
radiopharmaceuticals. There is no single radionuclide or BFCA that is optimal for all
applications in either imaging or treatment. The recent worldwide shortages experienced
with the 99Mo/99mTc generator may show their after effects through development of
additional isotope production facilities or alternative methods to the production of 99Mo.
These shortages will likely also show their effects through the development of other
radionuclides and radiopharmaceuticals as alternatives to 99mTc based diagnostic imaging
agents. There is much recent interest in 18F and 68Ga based agents as PET alternatives
to 99mTc. The development of multimodality imaging agents (MRI and PET/SPECT)[169,
170] and radiolabeled nanoparticle imaging agents[171] were not included in this paper,
however these are two of the new up and coming areas about which we will likely see much
more in the future.
Radiotherapeutic agents hold hope as alternatives to chemotherapeutic drugs in that the side
effects can be significantly less due to the very low concentrations of actual drug
administered (nM versus mM concentrations). However, delivery of sufficient radiation
dose to tumors without overburdening the non-target tissues continues to be an issue that
needs to be overcome.
All of the radiometals discussed have both advantages and disadvantages regarding their
routine use. The nuclear properties (Table 1) of the radiometals make them useful for
radiopharmaceutical applications. Their availability in high specific activity (high activity/

unit mass) and their chemistry at the radiotracer level (often nM or less) have made their
routine use challenging. The interest in using a commercially available BFCA (i.e., DOTA
or DTPA analogs) rather than synthesizing an appropriate BFCA has increased interest in
the radiometals for which these BFCAs may be useful (e.g.,
radiolanthanides, 90Y, 111In, 67/68Ga, 64Cu) even when the resultant radiometal complex is
less than optimal (e.g., DOTA for Cu) in vivo. Suitable chelates as the basis of BFCAs are
lacking for the less used radiometals for which DOTA or DTPA will not serve as a useful
BFCA (e.g., 199Au, 105Rh, 89Zr, 67/68Ga). Addressing the issues of isotope availability, high
specific activity, and appropriate BFCA technology in this field for the various radiometals

will be critical for the development of the next generation of radiopharmaceuticals for use in
nuclear medicine.
Acknowledgments
We would like to acknowledge NIBIB Training Grant 5 T32 EB004822 (V.C and D.W.D.), support from the U.S.
Department of Veterans Affairs Research Career Scientist Award (T.J.H.) and editorial/technical support from
Tammy L. Rold.
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Figure 1.
Structure of Cardiolite.

Figure 2.
Cartoon of a generic bifunctional chelating agent.

Figure 3.
Structures of (A) Neurolite, (B) Ceretec, (C) Myoview, and (D) MAG3.

Figure 4.
Structures of (A) TcN-NOET and (B) TcN(S2)(PNP)+.

Figure 5.
Structures of (A) 99mTc-depreotide and (B) 99mTc-HYNIC-GRP peptide.

Figure 6.
Structure of Teboroxime.

Figure 7.
99mTc(I)tricarbonyl complexes anchored by (A) tris(pyrazoyl)methane and (B) histadine (X
= CH2, N) functionalized tridentate chelates.


Figure 8.
Structure of Re-N2S2-IMP 1.

Figure 9.
Structures of (A) Quadramet and (B) Octreoscan.

Figure 10.
Structure of [Au(3,4-HxTSE)]

Table 1
Radionuclide properties (National Nuclear Data Center, http://www.nndc.bnl.gov)

Radionuclide Decay path and maximum Gamma emission (%) Half-life

particle emission (%)
Cu-62 2.926 MeV + (97.4%) 511 keV (194.9) 9.74 min
EC decay (2.6%)
Cu-64 0.653 MeV + (17.6%) 511 keV (35.2) 12.7 h

EC decay (43.9%)
0.579 MeV (38.5%)
Cu-67 0.562 MeV 184.6 keV (48.7) 2.58 d

93.3 keV (16.1)
91.3 keV (7)
Ga-67 EC decay 393.5 keV (4.6) 3.2617 d

300 keV (16.6)
184.6 keV (21.4)
93.3 keV (38.8)
Ga-68 0.836 MeV + (90%) 1077 keV (3 %) 67.71 min
EC decay (10%) 511 keV (178.3%)
Zr-89 0.902 MeV + (22.74%) 511 keV (45.5) 3.27 d

EC Decay (77.26%) 909 keV (99)
Y-90 2.28 MeV 64.053 h
Tc-99m IT 140 keV (89) 6.0067 h
Rh-105 0.5672 MeV 318.9 keV (19.1) 35.36 h
In-111 EC decay 245 keV (94.1) 2.8047 d

171 keV (90.7)
Pm-149 1.072 MeV (95.9%) 286 keV (3.1) 53.08 h
Sm-153 0.8076 MeV 103 keV (29.25) 46.50 h
Tb-161 0.593 MeV 74.6 keV (10.2) 6.89 d
Dy-166 0.4868 MeV 82.5 keV (13) 81.6 h
Ho-166 1.8547 MeV 80.57 keV (6.56) 26.824 h
Lu-177 0.498 MeV 208.4 keV (10.36) 6.647 d

112.95 keV (6.17)
Re-186 1.07 MeV 137.2 keV (9.47) 3.7186 d
Re-188 2.12 MeV 155 keV (15.6) 17.003 h
Au-198 1.372 MeV 411.8 keV (95.62) 2.695 d

Au-199 0.452 MeV 208.2 keV (8.72) 3.139 d

158.4 keV (40)
Bi-212 2.252 MeV (64.06%) 727.3 keV (6.67) 60.55 min

6.09 MeV (35.94%)
8.78 MeV (Po-212)
Bi-213 1.423 MeV (97.8%) 440.5 keV (25.94) 45.59 min

5.87 MeV (2.1%)
8.375 MeV (Po-213)
Ac-225 5.83 MeV 99 keV (5.8) 10 d
6.34 MeV (Fr-221)
7.07 MeV (At-217)
1.423 MeV (Bi-213)

Table 2
Peptides and peptide receptors currently under evaluation as biological targeting vectors in diagnostic and
therapeutic radiopharmaceuticals
Peptide Receptor Tumor expression

Somatostatin (SST) Somatostatin receptor subtype 2 (SST2) Neuroendocrine including gastroenteropancretic,
carcinoids, pituitary, breast, brain, small cell lung cancer
Bombesin (BBN) / Gastrin Bombesin receptor subtype 2 (BB2) Prostate, breast, pancreas, small cell lung, colorectal
Releasing Peptide (GRP)
-Melanotropin (MSH) Melanocortin-1 receptor (MC1R) Melanomas
Neurotensin (NT) Nuerotensin receptor (NTR1) Colon, Ewings sarcoma, breast, exocrine pancreatic
cancer
Neuropeptide Y (NPY) Neuropeptide receptor Y1 (Y-1) Breast cancer, ovary, adrenal, brain, kidney, Ewings
sarcoma
Cholecystokinin (CCK) Cholecystokinin-B (CCK-B) Small cell lung cancer, medullary thyroid cancer,
astrocytomas
Arg-Gly-Asp (RGD) V3 integrin Tumor angiogenesis in melanoma, ovarian, lung

carcinoma, neuroblastomas, glioblastomas, breast cancer

Norganic Chemistry in Nuclear Imaging and Radiotherapy - Current and Future Direction

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Radiochim Acta. 2012 August ; 100(8-9): 653667. doi:10.1524/ract.2012.1964.

Inorganic chemistry in nuclear imaging and radiotherapy:

available at a reasonable cost.

and associated problems. Technetium-99m was considered to be the ideal diagnostic

Radiochim Acta. Author manuscript; available in PMC 2014 November 06.

in concentration or lower, pose challenges. The availability of a matched pair of

Targeting strategies for radiometal conjugates

Radiochim Acta. Author manuscript; available in PMC 2014 November 06.

An example of a bioconjugate under current investigation is the bombesin peptide

Radiometal chelate considerations

Radiochim Acta. Author manuscript; available in PMC 2014 November 06.

many approved Tc(V) radiopharmaceuticals such as Neurolite, Ceretec, Myoview and

Technetium(V) has a d2 electronic configuration and is dominated by oxo chemistry in

Radiochim Acta. Author manuscript; available in PMC 2014 November 06.

mercaptoacetylglycylglycylglycine derivatives (N3S MAG3 derivatives), diaminedithiol or

ligands as potential bifunctional chelates; only the [TcN(PXP)(YZ)]0/+ (and no

oxidation state desirable as the basis of new Tc radiopharmaceutical development. The

Radiochim Acta. Author manuscript; available in PMC 2014 November 06.

tricarbonyl core is given in Figure 7 [73, 75].

Radiochim Acta. Author manuscript; available in PMC 2014 November 06.

investigated predominantly as a surrogate to Tc(I) tricarbonyl complexes on the macroscopic

Radiochim Acta. Author manuscript; available in PMC 2014 November 06.

however these complexes have demonstrated limited in vivo stability. Cross-bridged

Since last reviewed, two NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) Cu-64

conjugates[107110] have been reported. The 64Cu- NO2A-8-AOC-BBN(714)NH2

Radiochim Acta. Author manuscript; available in PMC 2014 November 06.

Gallium, indium, radiolanthanides, bismuth and actinium

Approved radiopharmaceuticals incorporating these radiometals include Quadramet

Octreoscan (111In-DTPA-octreotide) for imaging somatostatin receptor positive cancers

Radiochim Acta. Author manuscript; available in PMC 2014 November 06.

Several radiolanthanides have nuclear properties suitable for radiotherapy applications

Yttrium(III) is often considered a pseudo-lanthanide as it is situated above La(III) in Group

Radiochim Acta. Author manuscript; available in PMC 2014 November 06.

Radiochim Acta. Author manuscript; available in PMC 2014 November 06.

Recently, Bottenus and co-workers investigated a series of gold(III) bis-thiosemicarbazone

Gold-198 nanoparticles have received recent attention for potential radiotherapeutic

Radiochim Acta. Author manuscript; available in PMC 2014 November 06.

P(CH2NHCH(CH3)COOH)3 (THPAL) to a mixture of 198AuCl4 and Gum Arabic under

Radiochim Acta. Author manuscript; available in PMC 2014 November 06.

complexation with Rh(III) (cis- and trans-dichloro, respectively) [159, 162].

radiopharmaceutical applications. Their availability in high specific activity (high activity/

Radiochim Acta. Author manuscript; available in PMC 2014 November 06.

5. Bhattacharyya S, Dixit M. Metallic radionuclides in the development of diagnostic and therapeutic

Radiochim Acta. Author manuscript; available in PMC 2014 November 06.

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Radiochim Acta. Author manuscript; available in PMC 2014 November 06.

Radiochim Acta. Author manuscript; available in PMC 2014 November 06.

A European Journal. 2010; 16:21152124.

Radiochim Acta. Author manuscript; available in PMC 2014 November 06.

Radiochim Acta. Author manuscript; available in PMC 2014 November 06.

structure with antioxidation stability. Bioconjugate Chemistry. 2005; 16:634643. [PubMed:

synthesis and toxicity of tripodal tricarbonyl rhenium complexes as radiopharmaceutical models.

of Biological Inorganic Chemistry. 2003; 8:217225. [PubMed: 12459917]

Radiochim Acta. Author manuscript; available in PMC 2014 November 06.

tumour targeting. Chemistry - A European Journal. 2008; 14:30263034.

Radiochim Acta. Author manuscript; available in PMC 2014 November 06.

Molecular Imaging. 2010; 9:120. [PubMed: 20128994]

developments in 68Ga radiopharmaceutical chemistry. Current Topics in Medicinal Chemistry.

Radiochim Acta. Author manuscript; available in PMC 2014 November 06.

ImmunoPET of prostate-specific membrane antigen expression in vivo. The Journal of Nuclear

Radiochim Acta. Author manuscript; available in PMC 2014 November 06.

Radiochim Acta. Author manuscript; available in PMC 2014 November 06.